Theranostic in GLP-1R molecular imaging: challenges and emerging opportunities

Abstract

Theranostic in nuclear medicine combines diagnostic imaging and internal irradiation therapy using different therapeutic nuclear probes for visual diagnosis and precise treatment. GLP-1R is a popular receptor target in endocrine diseases, non-alcoholic steatohepatitis, tumors, and other areas. Likewise, it has also made breakthroughs in the development of molecular imaging. It was recognized that GLP-1R imaging originated from the study of insulinoma and afterwards was expanded in application including islet transplantation, pancreatic β-cell mass measurement, and ATP-dependent potassium channel-related endocrine diseases. Fortunately, GLP-1R molecular imaging has been involved in ischemic cardiomyocytes and neurodegenerative diseases. These signs illustrate the power of GLP-1R molecular imaging in the development of medicine. However, it is still limited to imaging diagnosis research in the current molecular imaging environment. The lack of molecular-targeted therapeutics related report hinders its radiology theranostic. In this article, the current research status, challenges, and emerging opportunities for GLP-1R molecular imaging are discussed in order to open a new path for theranostics and to promote the evolution of molecular medicine.

Keywords: GLP-1r; challenges; molecular imaging; opportunities; theranostics.

FIGURE 1

The expression of GLP-1/GLP-1R agonists in different organs and tissues. GLP1R is widely distributed and is expressed in both islets and beta cells of the pancreas, adipose tissue, heart, liver, kidney and gastroduodenum. It is also found in the frontal lobe, substantia nigra, hypothalamus and limbic system of the brain. They perform their respective functions in different tissue sites.

FIGURE 2

The schematic of GLP-1R molecular imaging. GLP1 analogues can bind competitively with GLP1 to GLP-1R targets and achieve GLP-1R molecular imaging by labelling with different radionuclides. Many studies of GLP-1R molecular imaging have been performed in tumours such as insulinoma, medullary thyroid cancer, myocardial ischaemia, islet transplantation, pancreatic beta-cell mass monitoring, congenital hyperinsulinemia and neurodegenerative diseases.

FIGURE 3

Synthesis scheme of monomeric and dimeric exendin-4 analogs. Two novel peptide structures BaMalSar-exendin-4 (A) and Mal2Sar-(exendin-4)₂ (B) were respectively prepared by coupling the ligand Cys-exendin-4 with BaMalSar and Mal2Sar, in over 90% yield.

FIGURE 4

Schematic representation of the peptides investigated in the study. The top shows Ex4DFO and the bottom shows Ex4NOD. The chelators are depicted without coordinated radiometal.

FIGURE 5

GLP-1R molecular imaging of double-primary insulinomas. Two insulinoma lesions in the tail of the pancreas, only one of which was detected in conventional imaging.68 Ga-DOTA-exendin-4 molecular imaging successfully detected both lesions and guided surgical resection. In the axial images [(A) PET, (B) CT, (C) fusion) in addition to the significantly higher uptake of the lesion in the tail of the pancreas, we see that GLP-1R imaging successfully detected the other lesion adjacent to the kidney, which was not detected in the MRI image due to the obscuration of the kidney. Thus, GLP-1R molecular imaging offers better advantages over conventional imaging in the preoperative precise localization of insulinomas.

FIGURE 6

Scheme for the synthesis of [18F]AlF-NOTA-MAL-Cys39-exendin-4. Modified by coupling Cys39-exendin-4 to NOTA-MAL by addition of ionized target water containing 18F (740 MBq). Heated at 100°C for 10 min. Cool and dilute the mixture with sterile water and inject into a validated Varian BondElut C18 cartridge. 10 mL of sterile water washes the column twice and ethanol hydrochloride (0.3 mL) elutes the labelled peptide.

FIGURE 7

Commonly used chelating agents in GLP-1R molecular probes. The most classic chelators, DOTA, DTPA and the ^99mTc HYNIC chelator, which were used in the first GLP-1R molecular imaging studies, have all been successfully translated and used in clinical studies. On this basis, the advantages of ⁶⁸Ga radionuclides in GLP-1R imaging have been highlighted. New chelators, including DO3A, NOTA and NODAGA, are also beginning to make their mark in GLP-1R molecular imaging.